Dexmedetomidine premix formulation

ABSTRACT

The presently disclosed subject matter relates to pharmaceutical compositions comprising dexmedetomidine or a pharmaceutically acceptable salt thereof wherein the composition is formulated as a liquid for parenteral administration to a subject, and wherein the composition is disposed within a sealed container as a premixture. The pharmaceutical compositions can be used, for example, in perioperative care of a patient or for sedation.

I. FIELD OF THE INVENTION

The present invention relates to patient-ready, premixed formulations ofdexmedetomidine, or a pharmaceutically acceptable salt thereof, that canbe used, for example, in perioperative care of a patient or forsedation.

2. BACKGROUND OF THE INVENTION

Racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, which is knownunder the name medetomidine, is a selective and potent α₂-adrenoceptoragonist. Medetomidine has been used as an antihypertensive agent and asa sedative-analgesic agent. It has further been observed that thiscompound also possesses anxiolytic effects and can therefore be used inthe treatment of general anxiety, panic disorder and various types ofwithdrawal symptoms.

The d-enantiomer of medetomidine, the generic name of which isdexmedetomidine, is described in U.S. Pat. No. 4,910,214 as anα₂-adrenoceptor agonist for general sedation/analgesia and the treatmentof hypertension or anxiety. U.S. Pat. Nos. 5,344,840 and 5,091,402discuss dexmedetomidine in perioperative and epidural use, respectively.For example, when used in perioperative care, dexmedetomidine can reducethe amount of anesthetic necessary to anesthetize a patient.Additionally, U.S. Pat. No. 5,304,569 discusses the use ofdexmedetomidine in treating glaucoma, and U.S. Pat. No. 5,712,301discusses the use of dexmedetomidine for preventing neurodegenerationcaused by ethanol consumption. Furthermore, U.S. Pat. No. 6,716,867discloses methods of sedating a patient while in an intensive care unitby administering dexmedetomidine, or a pharmaceutically acceptable saltthereof, to the patient.

Dexmedetomidine can be administered to a patient in a variety of ways.For example, U.S. Pat. Nos. 4,544,664 and 4,910,214 disclose theadministration of dexmedetomidine via parenteral, intravenous, and oralroutes. U.S. Pat. No. 4,670,455 describes intramuscular and intravenousadministration, while U.S. Pat. Nos. 5,124,157 and 5,217,718 describe amethod and device for administering dexmedetomidine through the skin.Additionally, U.S. Pat. No. 5,712,301 states that dexmedetomidine can beadministered transmucosally.

To date, dexmedetomidine has been provided as a concentrate that must bediluted prior to administration to a patient. The requirement of adilution step in the preparation of the dexmedetomidine formulation isassociated with additional costs and inconvenience, as well as the riskof possible contamination or overdose due to human error. Thus, adexmedetomidine formulation that avoids the expense, inconvenience,delay and risk of contamination or overdose would provide significantadvantages over currently available concentrated formulations.

3. SUMMARY OF THE INVENTION

The present invention relates to premixed pharmaceutical compositions ofdexmedetomidine, or a pharmaceutically acceptable salt thereof, that areformulated for administration to a patient, without the need toreconstitute or dilute the composition prior to administration. Thus,the compositions of the present invention are formulated as a premixedcomposition comprising dexmedetomidine.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition is a liquid comprising dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of betweenabout 0.05 μg/mL and about 15 μg/mL.

In other non-limiting embodiments, the premixed dexmedetomidinecomposition is a liquid comprising dexmedetomidine at a concentration ofabout 4 μg/mL.

In other non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine mixed or dissolved in a sodiumchloride saline solution.

In certain embodiments, the premixed dexmedetomidine composition isdisposed within a sealed container or vessel.

In certain embodiments, the dexmedetomidine composition is disposed in acontainer or vessel and is formulated as a premixture.

In certain embodiments, the premixed dexmedetomidine composition isdisposed within a sealed container as a total volume of about 20 mL, 50mL or 100 mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention comprises dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of betweenabout 0.05 μg/mL and about 15 μg/mL, and sodium chloride at aconcentration of between about 0.01 and about 2.0 weight percent.

In other non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention comprises dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of about 4μg/mL and sodium chloride at a concentration of about 0.90 weightpercent.

In certain embodiments, the compositions of the present invention areformulated as a pharmaceutical composition for administration to asubject for sedation, analgesia or treatment of anxiety or hypertension.

The present invention also relates to the perioperative treatment of apatient to reduce the response of the autonomic nervous system tostimuli during an operation by administering a dexmedetomidinecomposition of the invention.

In other non-limiting embodiments, the dexmedetomidine compositions ofthe present invention can be administered as an anxiolytic analgesic toa patient. In certain embodiments, the composition can be administeredas a premedication prior to an operation with or without administrationof an amount of an anesthetic effective to achieve a desired level oflocal or general anesthesia.

In other non-limiting embodiments, the dexmedetomidine compositions ofthe present invention can be administered as a sedative. In certainembodiments, the composition is administered preoperatively topotentiate the effect of an anesthetic, wherein administration of thecomposition reduces the amount of anesthetic required to achieve adesired level of anesthesia.

In certain embodiments of the present invention, the premixeddexmedetomidine composition is administered parenterally as a liquid,orally, transdermally, intravenously, intramuscularly, subcutaneously,or via an implantable pump.

4. DETAILED DESCRIPTION

The present invention is based in part on the discovery thatdexmedetomidine prepared in a premixed formulation that does not requirereconstitution or dilution prior to administration to a patient, remainsstable and active after prolonged storage. Such premixed formulationstherefore avoid the cost, inconvenience, and risk of contamination oroverdose that can be associated with reconstituting or diluting aconcentrated dexmedetomidine formulation prior to administration to apatient.

For clarity and not by way of limitation, this detailed description isdivided into the following sub-portions:

(4.1) Definitions;

(4.2) Pharmaceutical formulations; and

(4.3) Methods of using premixed dexmedetomidine compositions.

4.1 Definitions

The terms used in this specification generally have their ordinarymeanings in the art, within the context of this invention and in thespecific context where each term is used. Certain terms are discussedbelow, or elsewhere in the specification, to provide additional guidanceto the practitioner in describing the compositions and methods of theinvention and how to make and use them.

According to the present invention, the term “dexmedetomidine” as usedherein refers to a substantially pure, optically active dextrorotarystereoisomer of medetomidine, as the free base or pharmaceuticallyacceptable salt. In one, non-limiting embodiment, dexmedetomidine hasthe formula (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole. Apharmaceutically acceptable salt of dexmedetomidine can includeinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,and salicylic acid. Preferably, the dexmedetomidine salt isdexmedetomidine HCl. In other non-limiting embodiments, dexmedetomidinecomprises the structure depicted below in Formula I:

The terms “premix” or “premixture” as used herein refers to apharmaceutical formulation that does not require reconstitution ordilution prior to administration to a patient. For example, in contrastto non-premixed formulations of dexmedetomidine, the premixedcompositions provided herein are suitable for administration to apatient without dilution by, for example, a clinician, hospitalpersonnel, caretaker, patient or any other individual.

In certain embodiments, the compositions of the present invention can beformulated as “ready to use” compositions which refer to premixedcompositions that are suitable for administration to a patient withoutdilution. For example, in certain embodiments, the compositions of thepresent invention are “ready to use” upon removing the compositions froma sealed container or vessel.

In certain embodiments, the compositions of the present invention can beformulated as a “single use dosage,” which refers to a premixedcomposition that is disposed within a sealed container or vessel as aone dose per container or vessel formulation.

According to the invention, a “subject” or “patient” is a human, anon-human mammal or a non-human animal. Although the animal subject ispreferably a human, the compounds and compositions of the invention haveapplication in veterinary medicine as well, e.g., for the treatment ofdomesticated species such as canine, feline, and various other pets;farm animal species such as bovine, equine, ovine, caprine, porcine,etc.; wild animals, e.g., in the wild or in a zoological garden; andavian species, such as chickens, turkeys, quail, songbirds, etc.

The term “purified” as used herein refers to material that has beenisolated under conditions that reduce or eliminate the presence ofunrelated materials, i.e., contaminants, including native materials fromwhich the material is obtained. As used herein, the term “substantiallyfree” is used operationally, in the context of analytical testing of thematerial. Preferably, purified material substantially free ofcontaminants is at least 95% pure; more preferably, at least 97% pure,and more preferably still at least 99% pure. Purity can be evaluated,for example, by chromatography or any other methods known in the art. Ina specific embodiment, purified means that the level of contaminants isbelow a level acceptable to regulatory authorities for safeadministration to a human or non-human animal.

The term “pharmaceutically acceptable,” when used in connection with thepharmaceutical compositions of the invention, refers to molecularentities and compositions that are physiologically tolerable and do nottypically produce untoward reactions when administered to a human.Preferably, as used herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, dispersingagent or vehicle with which the compound is administered. Suchpharmaceutical carriers can be sterile liquids, such as water and oils.For example, water, aqueous solutions, saline solutions, aqueousdextrose or glycerol solutions can be employed as carriers, particularlyfor injectable solutions. Suitable pharmaceutical carriers are describedin, for example, “Remington's Pharmaceutical Sciences” by Philip P.Gerbino, 21st Edition (or previous editions).

The term “pharmaceutical composition” as used in accordance with thepresent invention relates to compositions that can be formulated in anyconventional manner using one or more pharmaceutically acceptablecarriers or excipients. A “pharmaceutically acceptable” carrier orexcipient, as used herein, means approved by a regulatory agency of theFederal or a state government, or as listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in mammals, and moreparticularly in humans.

The term “dosage” is intended to encompass a formulation expressed interms of μg/kg/day, μg/kg/hr, mg/kg/day or mg/kg/hr. The dosage is theamount of an ingredient administered in accordance with a particulardosage regimen. A “dose” is an amount of an agent administered to amammal in a unit volume or mass, e.g., an absolute unit dose expressedin mg or μg of the agent. The dose depends on the concentration of theagent in the formulation, e.g., in moles per liter (M), mass per volume(m/v), or mass per mass (m/m). The two terms are closely related, as aparticular dosage results from the regimen of administration of a doseor doses of the formulation. The particular meaning in any case will beapparent from context.

The terms “therapeutically effective dose,” “effective amount,” and“therapeutically effective amount” refer to an amount sufficient toproduce the desired effect.

In some non-limiting embodiments, a “therapeutically effective dose”means an amount sufficient to reduce by at least about 15%, preferablyby at least 50%, more preferably by at least 90%, and most preferablyprevent, a clinically significant deficit in the activity, function andresponse of the host. Alternatively, a therapeutically effective amountis sufficient to cause an improvement in a clinically significantcondition in the host. These parameters will depend on the severity ofthe condition being treated, other actions, such as diet modification,that are implemented, the weight, age, and sex of the subject, and othercriteria, which can be readily determined according to standard goodmedical practice by those of skill in the art.

In other non-limiting embodiments a therapeutic response may be anyresponse that a user (e.g., a clinician) will recognize as an effectiveresponse to the therapy. Thus, a therapeutic response will generally bean induction of a desired effect, such as, for example, sedation oranalgesia.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, preferably up to 10%, more preferably up to 5%,and more preferably still up to 1% of a given value. Alternatively,particularly with respect to biological systems or processes, the termcan mean within an order of magnitude, preferably within 5-fold, andmore preferably within 2-fold, of a value.

4.2 Pharmaceutical Compositions

The compounds and compositions of the invention may be formulated aspharmaceutical compositions by admixture with a pharmaceuticallyacceptable carrier or excipient. In certain non-limiting embodiments,the compounds or compositions are provided in a therapeuticallyeffective amount to an animal, such as a mammal, preferably a human, inneed of treatment therewith for inducing a sedative, anxiolytic,analgesic, or anesthetic effect.

In certain non-limiting embodiments, dexmedetomidine is formulated as acomposition, wherein the dexmedetomidine is the only therapeuticallyactive ingredient present in the composition. In another non-limitingembodiments, dexmedetomidine is formulated as a composition, wherein thedexmedetomidine is formulated in combination with at least one or moreother therapeutically active ingredient. The formulation is preferablysuitable for parenteral administration, including, but not limited to,intravenous, subcutaneous, intramuscular and intraperitonealadministration; however, formulations suitable for other routes ofadministration such as oral, intranasal, mucosal or transdermal are alsocontemplated.

The pharmaceutical formulations suitable for injectable use, such as,for example, intravenous, subcutaneous, intramuscular andintraperitoneal administration, include sterile aqueous solutions ordispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersion. In all cases, the form canbe sterile and can be fluid to the extent that easy syringabilityexists. It can be stable under the conditions of manufacture and storageand can be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, saline, ethanol, polyol (forexample, glycerol, propylene glycol, and polyethylene glycol, and thelike), suitable mixtures thereof, and oils. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The preventions of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, benzylalcohol, sorbic acid, and the like.

In many cases, it will be preferable to include isotonic agents, forexample, sugars or sodium chloride. Prolonged absorption of theinjectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonosterate and gelatin. Sterile injectable solutions may be prepared byincorporating the dexmedetomidine in the required amounts in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filter or terminal sterilization.Generally, dispersions are prepared by incorporating the varioussterilized active ingredients into a sterile vehicle which contains thebasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze-drying technique which yield a powder ofthe active ingredient plus any additional desired ingredient frompreviously sterile-filtered solution thereof.

Preferably the formulation may contain an excipient. Pharmaceuticallyacceptable excipients which may be included in the formulation arebuffers such as citrate buffer, phosphate buffer, acetate buffer, andbicarbonate buffer; amino acids; urea; alcohols; ascorbic acid;phospholipids; proteins, such as serum albumin, collagen, and gelatin;salts such as EDTA or EGTA, and sodium chloride; liposomes;polyvinylpyrollidone; sugars, such as dextran, mannitol, sorbitol, andglycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000,PEG-6000); glycerol; glycine; lipids; preservatives; suspending agents;stabilizers; and dyes. As used herein, the term “stabilizer” refers to acompound optionally used in the pharmaceutical compositions of thepresent invention in order to avoid the need for sulphite salts andincrease storage life. Non-limiting examples of stabilizers includeantioxidants. Buffer systems for use with the formulations includecitrate; acetate; bicarbonate; and phosphate buffers.

The formulation also may contain a non-ionic detergent. Preferrednon-ionic detergents include Polysorbate 20, Polysorbate 80, TritonX-100, Triton X-114, Nonidet P-40, Octyl α-glucoside, Octyl β-glucoside,Brij 35, Pluronic, and Tween 20.

The parenteral formulations of the present invention can be sterilized.Non-limiting examples of sterilization techniques include filtrationthrough a bacterial-retaining filter, terminal sterilization,incorporation of sterilizing agents, irradiation, and heating.

The route of administration may be oral or parenteral, includingintravenous, subcutaneous, intra-arterial, intraperitoneal, ophthalmic,intramuscular, buccal, rectal, vaginal, intraorbital, intracerebral,intradermal, intracranial, intraspinal, intraventricular, intrathecal,intracisternal, intracapsular, intrapulmonary, intranasal, transmucosal,transdermal, or via inhalation.

Administration of the above-described parenteral formulations may be byperiodic injections of a bolus of the preparation, or may beadministered by intravenous or intraperitoneal administration from areservoir which is external (e.g., an intravenous bag) or internal(e.g., a bioerodable implant, a bioartificial or organ). See, e.g., U.S.Pat. Nos. 4,407,957 and 5,798,113, each incorporated herein by referencein their entireties. Intrapulmonary delivery methods and apparatus aredescribed, for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and5,814,607, each incorporated herein by reference in their entireties.Other useful parenteral delivery systems include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, pumpdelivery, encapsulated cell delivery, liposomal delivery,needle-delivered injection, needle-less injection, nebulizer,aeorosolizer, electroporation, and transdermal patch. Needle-lessinjector devices are described in U.S. Pat. Nos. 5,879,327; 5,520,639;5,846,233 and 5,704,911, the specifications of which are hereinincorporated herein by reference in their entireties. Any of theformulations described herein can be administered in these methods.

In yet another non-limiting embodiment, the therapeutic compound can bedelivered in a controlled or sustained release system. For example, acompound or composition may be administered using intravenous infusion,an implantable osmotic pump, a transdermal patch, liposomes, or othermodes of administration. In one embodiment, a pump may be used (seeSefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980,Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). Inanother embodiment, polymeric materials can be used (see Langer and Wiseeds., 1974, Medical Applications of Controlled Release, CRC Press: BocaRaton, Fla.; Smolen and Ball eds., 1984, Controlled DrugBioavailability, Drug Product Design and Performance, Wiley, N.Y.;Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem., 23:61;Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol.,25:351; Howard et al., 9189, J. Neurosurg. 71:105). In yet anotherembodiment, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., the brain, thus requiring only a fractionof the systemic dose (see, e.g., Goodson, 1984, in Medical Applicationsof Controlled Release, Vol. 2, pp. 115-138).

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine, or a pharmaceutically acceptablesalt thereof, at a concentration of between about 0.005 μg/mL and about100 μg/mL, or between about 0.005 μg/mL and about 50 μg/mL, or betweenabout 0.005 μg/mL and about 25 μg/mL, or between about 0.005 μg/mL andabout 15 μg/mL, or between about 0.005 μg/mL and about 10 μg/mL, orbetween about 0.005 μg/mL and about 7 μg/mL, or between about 0.005μg/mL and about 5 μg/mL, or between about 0.005 μg/mL and about 4 μg/mL,or between about 0.005 μg/mL and about 3 μg/mL, or between about 0.005μg/mL and about 2 μg/mL, or between about 0.005 μg/mL and about 1 μg/mL,or between about 0.005 μg/mL and about 0.5 μg/mL, or between about 0.005μg/mL and about 0.05 μg/mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine, or a pharmaceutically acceptablesalt thereof, at a concentration of between about 3.5 μg/mL and about4.5 μg/mL, or between about 3 μg/mL and about 5 μg/mL, or between about2.5 μg/mL and about 5.5 μg/mL, or between about 2 μg/mL and about 6μg/mL, or between about 1.5 μg/mL and about 6.5 μg/mL, or between about1 μg/mL and about 7 μg/mL, or between about 0.5 μg/mL and about 10μg/mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine at a concentration of about 0.5μg/mL, or about 1 μg/mL, or about 1.5 μg/mL, or about 2 μg/mL, or about2.5 μg/mL, or about 3 μg/mL, or about 3.5 μg/mL, or about 4 μg/mL, orabout 4.5 μg/mL, or about 5 μg/mL, or about 5.5 μg/mL, or about 6 μg/mL,or about 6.5 μg/mL, or about 7 μg/mL, or about 7.5 μg/mL, or about 8μg/mL, or about 8.5 μg/mL, or about 9 μg/mL, or about 9.5 μg/mL, orabout 10 μg/mL, or about 10.5 μg/mL, or about 11 μg/mL, or about 11.5μg/mL, or about 12 μg/mL, or about 12.5 μg/mL, or about 13 μg/mL, orabout 13.5 μg/mL, or about 14 μg/mL, or about 14.5 μg/mL, or about 15μg/mL, or about 15.5 μg/mL, or about 16 μg/mL, or about 16.5 μg/mL, orabout 17 μg/mL, or about 17.5 μg/mL, or about 18 μg/mL, or about 18.5μg/mL or about 19 μg/mL, or about 19.5 μg/mL, or about 20 μg/mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine at a concentration of about 4μg/mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition is formulated as a liquid.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition is formulated at a pH of between about 1 and about 10, orbetween about 1 and about 8, or between about 1 and about 6, or betweenabout 1 and about 4, or between about 1 and about 2. In othernon-limiting embodiments, the premixed dexmedetomidine composition isformulated at a pH of between about 2 and about 10, or between about 4and about 8, or between about 4 and about 7. In other non-limitingembodiments, the premixed dexmedetomidine composition is formulated at apH of between about 4.7 and about 6.2. In a preferred non-limitingembodiment, the premixed dexmedetomidine composition is formulated at apH of between about 4.5 and about 7.0.

In other non-limiting embodiments, the premixed dexmedetomidinecomposition comprises dexmedetomidine mixed or dissolved in a sodiumchloride saline solution. The saline solution can comprise sodiumchloride present at a concentration of between about 0.05 weight percentand about 10 weight percent, or between about 0.05 weight percent andabout 5 weight percent, or between about 0.05 weight percent and about 3weight percent, or between about 0.05 weight percent and about 2 weightpercent, or between about 0.05 weight percent and about 1 weightpercent. In one preferred, non-limiting embodiment, the sodium chlorideis present at a concentration of about 0.9 weight percent.

In certain embodiments, the weight percent of the saline solution is apercent weight/weight of the premix composition. In certain embodiments,the weight percent of the saline solution is a percent weight/volume ofthe premix composition.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention comprises dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of betweenabout 0.05 μg/mL and about 15 μg/mL, and sodium chloride at aconcentration of between about 0.01 and about 2.0 weight percent.

In other non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention comprises dexmedetomidine, or apharmaceutically acceptable salt thereof, at a concentration of about 4μg/mL and sodium chloride at a concentration of about 0.90 weightpercent.

In one non-limiting example, the 0.9% NaCl solution is formulated bymixing 9.0 g NaCl/1000 mL of water. In certain embodiments, the premixcompositions of the present invention are formulated by adding 0.118 gdexmedetomidine HCl plus 9.0 g NaCl into the same 1000 mL of water. Thesolution can then be mixed with addition 0.9% NaCl solution to achieve adesired concentration of dexmedetomidine, for example, 4 μg/mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention is disposed in a container orvessel that can maintain the sterility of, or prevent the contaminationof, a premixed dexmedetomidine composition that is purified orsubstantially free of any contaminants. In certain non-limitingembodiments, the container or vessel is a sealed container or vessel.

In certain non-limiting embodiments, the dexmedetomidine composition ofthe present invention is disposed in a container or vessel and isformulated as a premixture.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention is disposed in a container orvessel and is formulated as a single use dosage. In certain non-limitingembodiments, the premixed dexmedetomidine composition of the presentinvention is disposed in a container or vessel and is formulated as adosage for multiple use.

In certain non-limiting embodiments, the container or vessel includes,but is not limited to, glass vials (for example, but not limited to,flint glass vials), ampoules, plastic flexible containers, for example,but not limited to, PVC (polyvinyl chloride) containers, VisIV™ plasticcontainers (Hospira, Inc., Lake Forest, Ill.), and CR3 elastomercopolyester ether containers (Hospira, Inc., Lake Forest, Ill.), CZresin containers, poly propylene containers and syringes.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention can be stored as a liquid in analiquot having a total volume of between about 1 and 500 mL, or betweenabout 1 and 250 mL, or between about 1 and 200 mL, or between about 1and 150 mL, or between about 1 and 125 mL, or between about 1 and 120mL, or between about 1 and 110 mL, or between about 1 and 100 mL, orbetween about 1 and 90 mL, or between about 1 and 80 mL, or betweenabout 1 and 70 mL, or between about 1 and 60 mL, or between about 1 and50 mL, or between about 1 and 40 mL, or between about 1 and 30 mL, orbetween about 1 and 20 mL, or between about 1 and 10 mL, or betweenabout 1 and 5 mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention can be stored as a liquid in analiquot having a total volume of about 5 mL, or about 10 mL, or about 15mL, or about 20 mL, or about 25 mL, or about 30 mL, or about 35 mL, orabout 40 mL, or about 45 mL, or about 50 mL, or about 55 mL, or about 60mL, or about 65 mL, or about 70 mL, or about 75 mL, or about 80 mL, orabout 85 mL, or about 90 mL, or about 95 mL, or about 100 mL, or about105 mL, or about 110 mL, or about 115 mL, or about 120 mL, or about 125mL, or about 130 mL, or about 135 mL, or about 140 mL, or about 145 mL,or about 150 mL, or about 200 mL, or about 250 mL, or about 500 mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention can be stored as a liquid in analiquot having a total volume of about 20 mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention can be stored as a liquid in analiquot having a total volume of about 50 mL.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition of the present invention can be stored as a liquid in analiquot having a total volume of about 100 mL.

4.3 Methods of Using Premixed Dexmedetomidine Compositions

In accordance with the invention, there are provided methods of using apremixed dexmedetomidine composition. In certain non-limitingembodiments, the present invention provides for preoperative treatmentof a patient to reduce the response of the autonomic nervous system tostimuli during an operation by administering a dexmedetomidinecomposition of the invention, as described in U.S. Pat. No. 5,344,840.In other non-limiting embodiments, the dexmedetomidine compositions ofthe present invention can be administered as a sedative. In certainembodiments, the composition is administered preoperatively topotentiate the effect of an anesthetic, wherein administration of thecomposition reduces the amount of anesthetic required to achieve adesired level of anesthesia. In certain embodiments, the dexmedetomidinecompositions of the present invention can be administered as ananxiolytic analgesic premedication prior to the operation with orwithout administration of an amount of an anesthetic effective toachieve a desired level of local or general anesthesia. In certainembodiments, the dexmedetomidine compositions of the present inventionare formulated as a pharmaceutical composition for use in a method ofsedation, analgesia or treatment of anxiety or hypertension.

In certain non-limiting embodiments, the patient treated with thepremixed dexmedetomidine composition of the invention is intubated. Thepatient may be intubated prior to, during, or after administration ofthe premixed dexmedetomidine composition. The patient may be intubatedby the nasotracheal, endotracheal, direct oral laryngoscopy or byfibreoptic routes, or via tracheotomy, for example, while being treatedin an intensive care unit (ICU), which, as used herein refers to anysetting that provides intensive care, as described, for example, in U.S.Pat. No. 6,716,867. For example, the compositions of the invention canbe used for sedating a patient in an intensive care unit which meansrendering a patient calm and treating conditions that affect patientcomfort, such as pain and anxiety, in any setting that providesintensive care.

In other non-limiting embodiments, the premixed dexmedetomidinecompositions of the present invention can be administered to a patientas a perioperative treatment. In certain embodiments, the compositioncan be administered as a premedication prior to an operation. In certainembodiments, the premixed dexmedetomidine compositions of the presentinvention can be used in the manufacture of a medicament forperioperative treatment of mammals to reduce the responses of theautonomic nervous system to stressful stimuli during an operation, forexample, as described in U.S. Pat. No. 5,344,840.

In other non-limiting embodiments, the premixed dexmedetomidinecompositions of the present invention can be administered to a patientas an adjunct anesthesia. For example, the composition can beadministered with or without an amount of an anesthetic effective toachieve a desired level of local or general anesthesia, for example, asdescribed in U.S. Pat. No. 5,344,840. In certain embodiments,administration of the compositions of the present invention reduces theamount of anesthetic required to achieve a desired level of anesthesia.

In other non-limiting embodiments, the patient treated with the premixeddexmedetomidine composition is critically ill. In one embodiment, thepatient suffers from one or more medical conditions. In certainembodiments, the medical condition is a lung problem, brain problem,heart problem, liver problem, kidney problem, eye or ear problem,gastrointestinal problem, or skin problem. Non-limiting examples of lungproblems include respiratory distress syndrome, pneumonia,bronchopulmonary dysplasia, apnea of prematurity, and pneumothorax.Non-limiting examples of brain problems include intraventricularhemorrhage, and cerebral palsy. Non-limiting examples of liver problemsinclude jaundice. Non-limiting examples of heart problems include patentductus arteriosus. Non-limiting examples of eye problems includeretinopathy of prematurity, myopia, and strabismus. Non-limitingexamples of other medical conditions includes heroin withdrawal, cocainewithdrawal, alcohol fetal syndrome, HIV-positive status, and Tay Sachsdisease.

In one embodiment, the patient has undergone surgery. The patient mayundergo surgery prior to, during, or after administration of thepremixed dexmedetomidine composition. Non-limiting examples of surgeryinclude cardiopulmonary bypass.

In other non-limiting embodiments, the premixed dexmedetomidinecompositions of the present invention can be administered to a patientas an anxiolytic or analgesic agent, for example, as described in U.S.Pat. Nos. 5,344,840 and 6,716,867. In one non-limiting example, themethod comprises local epidural or intraspinal administration of thepremixed dexmedetomidine composition of the invention.

In other non-limiting embodiments, the premixed dexmedetomidinecompositions of the present invention can be administered to a patientto lower intraocular pressure, for example, in the treatment ofglaucoma, as described in U.S. Pat. No. 5,304,569.

In certain embodiments, the premixed dexmedetomidine compositions of thepresent invention do not include any other active ingredient, ortherapeutic agent, other than dexmedetomidine.

In certain non-limiting embodiments of the present invention, thepremixed dexmedetomidine composition can be administered as a singlecontinuous dose over a period of time. For example, the premixeddexmedetomidine composition can be administered intravenously for aperiod of time of between about 1 and about 10 minutes, or between about1 and about 20 minutes, or between about 1 and about 30 minutes, orbetween about 1 and about 2 hours, or between about 1 and about 3 hours,or between about 1 and about 4 hours, or between about 1 and about 5hours, or between about 1 and about 6 hours, or between about 1 andabout 7 hours, or between about 1 and about 8 hours, or between about 1and about 9 hours, or between about 1 and about 10 hours, or betweenabout 1 and about 11 hours, or between about 1 and about 12 hours, orbetween about 1 and about 13 hours, or between about 1 and about 14hours, or between about 1 and about 15 hours, or between about 1 andabout 16 hours, or between about 1 and about 17 hours, or between about1 and about 18 hours, or between about 1 and about 19 hours, or betweenabout 1 and about 20 hours, or between about 1 and about 21 hours, orbetween about 1 and about 22 hours, or between about 1 and about 23hours, or between about 1 and about 24 hours, and administered at adosage of between about 0.005 μg/kg/hr and about 5 μg/kg/hr, or betweenabout 0.005 μg/kg/hr and about 4.5 μg/kg/hr, or between about 0.005μg/kg/hr and about 3 μg/kg/hr, or between about 0.005 μg/kg/hr and about2.5 μg/kg/hr, or between about 0.005 μg/kg/hr and about 2 μg/kg/hr, orbetween about 0.005 μg/kg/hr and about 1.5 μg/kg/hr, or between about0.005 μg/kg/hr and about 1 μg/kg/hr, or between about 0.005 μg/kg/hr andabout 0.5 μg/kg/hr, or between about 0.005 μg/kg/hr and about 0.25μg/kg/hr.

In other non-limiting embodiments of the present invention, the premixeddexmedetomidine composition can be administered as a loading dosefollowed by a maintenance dose over a period of time. For example, theloading dose can comprise administration of the premixed dexmedetomidinecomposition at a first dosage amount for a first period of time,followed by administration of the maintenance dose at a second dosageamount for a second period of time. The loading dose can be administeredfor a period of time of between about 1 and about 5 minutes, or betweenabout 1 and about 10 minutes, or between about 1 and about 15 minutes,or between about 1 and about 20 minutes, or between about 1 and about 25minutes, or between about 1 and about 30 minutes, or between about 1 andabout 45 minutes, or between about 1 and about 60 minutes. Following theloading dose, the maintenance dose can be administered for a period oftime as described above for a single continuous dose.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition, when administered as a single continuous, loading ormaintenance dose, is administered for a period of time of about 1 hourto about 7 days, or about 1 hour to about 4 days, or about 1 hour toabout 48 hours, or about 1 hour to about 36 hours, or about 1 hour toabout 24 hours, or about 1 hour to about 12 hours.

In certain non-limiting embodiments, the premixed dexmedetomidinecomposition, when administered as a single continuous, loading ormaintenance dose, is administered for a period of time of about 24 hoursto about 120 hours, or about 24 hours to about 108 hours, or about 24hours to about 96 hours, or about 24 hours to about 72 hours, or about24 hours to about 48 hours, or about 24 hours to about 36 hours.

When administered as a loading dose followed by a maintenance dose, theloading dose and/or maintenance dose can be a dose of between about0.005 μg/kg/hr and about 5 μg/kg/hr, or between about 0.005 μg/kg/hr andabout 4.5 μg/kg/hr, or between about 0.005 μg/kg/hr and about 3μg/kg/hr, or between about 0.005 μg/kg/hr and about 2.5 μg/kg/hr, orbetween about 0.005 μg/kg/hr and about 2 μg/kg/hr, or between about0.005 μg/kg/hr and about 1.5 μg/kg/hr, or between about 0.005 μg/kg/hrand about 1 μg/kg/hr, or between about 0.005 μg/kg/hr and about 0.5μg/kg/hr, or between about 0.005 μg/kg/hr and about 0.25 μg/kg/hr.

In a preferred non-limiting embodiment, the premixed dexmedetomidinecomposition is administered as a loading dose followed by a maintenancedose, wherein the loading dose is about 1 μg/kg/hr for a period of about10 minutes, followed by a maintenance dose of between about 0.2 μg/kg/hrto about 1 μg/kg/hr, more preferably, between about 0.2 μg/kg/hr toabout 0.7 μg/kg/hr.

In other preferred non-limiting embodiments, the premixeddexmedetomidine composition is administered as a loading dose followedby a maintenance dose, wherein the loading dose is about 0.5 μg/kg/hrfor a period of about 10 minutes, followed by a maintenance dose ofbetween about 0.2 μg/kg/hr to about 1 μg/kg/hr, more preferably, betweenabout 0.2 μg/kg/hr to about 0.7 μg/kg/hr.

In certain non-limiting embodiments, the dosage of premixeddexmedetomidine composition administered as a single continuous, loadingor maintenance dose, is titrated until a desired effect is achieved.

In some patients, the quality of the sedation achieved by administeringthe premixed dexmedetomidine composition of the present invention can beunique. In one non-limiting example, a patient sedated by the premixeddexmedetomidine composition is arousable and oriented. The patient canbe awakened and is able to respond to questions. The patient is awareand can tolerate an endotracheal tube. Should a deeper level of sedationbe required or desired, an increase in dose of the composition of theinvention can be administered to transit the patient into a deeper levelof sedation.

In certain non-limiting embodiments, the compositions of the inventioncan be administered to non-ventilated patients who require sedation,anxiolysis, analgesia, or hemodynamic stability in an amount to achievea sedative, anxiolytic, analgesic or hemodynamic stabilizing effect inthe patient.

5. EXAMPLES

The following examples are merely illustrative of the presentlydisclosed subject matter and they should not be considered as limitingthe scope of the invention in any way.

Example 1 Selection of Packaging Components for the PremixedDexmedetomidine Pharmaceutical Composition

In order to identify suitable primary packaging components for the 4μg/mL premixed dexmedetomidine composition in 0.9% NaCl, stabilitystudies were conducted in various configurations including glass vials,ampoules, plastic flexible containers (CR3 elastomer copolyester ethercontainers (Hospira, Inc., Lake Forest, Ill.), PVC and VisIV™ plasticcontainers (Hospira, Inc., Lake Forest, Ill.)), and Ansyr® syringes(Hospira, Inc., Lake Forest, Ill.). A batch of premixed dexmedetomidinecomposition was prepared at the premix concentration of 4 μg/mL, in 0.9%NaCl. Solution was filled into 20 mL ampoules, 50 mL glass vials, 100 mLPVC flexible containers, 100 mL CR3 elastomer copolyester ether flexiblecontainers (Hospira, Inc., Lake Forest, Ill.), 50 mL VisIV™ plastic(Hospira, Inc., Lake Forest, Ill.) flexible containers, and 10 mL Ansyr®syringes (Hospira, Inc., Lake Forest, Ill.), and all configurations wereautoclaved. The pH and potency (using HPLC method) of the sterilizedsamples were determined. The stability of the autoclaved samples underaccelerated conditions (40° C./75% RH) was also evaluated over a periodof 5 months (Table 1).

Potency was evaluated using a HPLC method. Post sterilization potencyvalues ranged from 73-88%. The solution pHs varied from 4.7-6.2following an in-process result of 6.0. Two weeks samples stored underambient conditions were tested for pH, potency and related substances.The two weeks potency results were considered as time zero resultsbecause the 4 μg/mL formulation remains stable at room temperature formore than 2 weeks. Comparison of potency results at time zero indifferent configurations indicated a drop in potency of premixeddexmedetomidine composition filled in CR3 elastomer copolyester etherbags (Hospira, Inc., Lake Forest, Ill.) and VisIV™ plastic bags(Hospira, Inc., Lake Forest, Ill.), after sterilization (Table 1).

The stability of the autoclaved samples under accelerated conditions(40° C./75% RH) was also evaluated over a period of 5 months (Table 1).After five months under accelerated conditions the potency of thepremixed dexmedetomidine composition in glass ampoules and vialsremained at about 98% while that in the syringe was found to be about90%. In PVC and CR3 elastomer copolyester ether bags (Hospira, Inc.,Lake Forest, Ill.), after the initial potency loss no further loss ofpotency was observed during the five month period.

TABLE 1 4 μg/mL Premixed Dexmedetomidine Composition in Normal SalineFormulation Stability 2 1 2 3 5 Week/ Month/ Month/ Month/ Month/ 25° C.40° C. 40° C. 40° C. 40° C. Avg Avg Avg Avg Avg Potency Potency PotencyPotency Potency ( % ) pH ( % ) pH (%) (%) (%) Ampoule 99.0 5.0 99.0 5.697.7 98.3 98.7 Vial 98.2 6.7 99.4 6.3 98.0 98.3 98.6 Syringe 95.0 5.594.6 5.7 92.2 89.5 90.8 CR3 80.2 4.7 79.5 4.8 NT 75.3 79.2 PVC 79.9 4.881.4 4.6 NT 79.0 76.7 Vis-IV ™ 95.8 5.9 92.8 5.8 NT 94.0 NT NT—Nottested

The cause of potency loss in PVC bags and CR3 elastomer copolyesterether bags (Hospira, Inc., Lake Forest, Ill.) during autoclaving wasinvestigated. Related substances testing on autoclaved premixeddexmedetomidine composition filled in PVC and CR3 elastomer copolyesterether bags (Hospira, Inc., Lake Forest, Ill.) revealed that potency dropdid not occur due to degradation, because the total percent ofimpurities was much less than 20% (Table 2). Loss of potency may be dueto either adsorption (restricted to the surface of the flex bag) and/orabsorption (not restricted to the surface) of the drug in to the flexbags. To confirm the absorption/adsorption phenomena, the CR3 elastomercopolyester ether bags (Hospira, Inc., Lake Forest, Ill.) and PVC bagsthat showed 20% potency loss were emptied and rinsed with MeOH. Therinse solvent was tested for dexmedetomidine. Nearly all the drug wasrecovered from CR3 elastomer copolyester ether bags (Hospira, Inc., LakeForest, Ill.)—indicating adsorption and only 1% of the drug wasrecovered from PVC bags—indicating absorption, since drug dissolves inDEHP.

The related substances results indicated that premixed dexmedetomidinecomposition in VisIV™ plastic bags (Hospira, Inc., Lake Forest, Ill.)had high impurity levels (Table 2), higher than levels observed inampoules, vials, syringes, PVC bags and CR3 elastomer copolyester etherbags (Hospira, Inc., Lake Forest, Ill.).

TABLE 2 Impurity Results for 4 μg/mL Premixed DexmedetomidineComposition 2 week/25° C. 1 Month/40° C. Total impurity (%) Totalimpurity (%) Ampoule 0.66% 0.54% Vial 0.02% NT Syringe 0.49% 1.48% CR32.61% 5.88% PVC 2.26% NT VisIV ™ 19.08% 7.02%

Example 2 Development in ADDVantage® PVC (Hospira, Inc., Lake Forest,Ill.) Admixture System

In this study three 250 mL ADDVantage® PVC bags (Hospira, Inc., LakeForest, Ill.) were spiked with 10 mL of dexmedetomidine concentrate (100μg/mL) to obtain a final concentration of 4 μg/mL. As a control, a glassbottle was spiked in the same manner. Upon thorough mixing of thesamples, an aliquot was withdrawn for subsequent potency analysis. Thebag was then allowed to sit on the bench top for various intervaltesting. The results showed that there is a drop in potency after theinitial mixing period and a slight decrease thereafter (Table 3).

TABLE 3 4 μg/mL Premixed Dexmedetomidine Composition ADDVantage ® PVCbag (Hospira, Inc., Lake Forest, IL) Admixture Study Time FollowingAdmixture % Loss from Control* Immediately 5.3 4 Hours 5.6 8 Hours 6.024 Hours 5.5 48 Hours 5.8 72 Hours 6.0 7 Days 6.1 *Average of threespiked bags compared to glass bottle.

Example 3 Modification of the Premixed Dexmedetomidine CompositionFormulation

The pH of the premixed dexmedetomidine composition formulation canaffect the adsorption of dexmedetomidine molecule. The free base form ofdexmedetomidine is more adsorptive. At lower pH ˜4.0, most of thedexmedetomidine is in the ionized form, which minimized adsorption andthereby loss in potency. Buffered formulations were tested to determinewhether loss of potency in flex bags can be minimized.

Buffered formulations were prepared at different pHs 3.0, 3.4, 4.0, and4.5 using acetate, citrate, lactate and ascorbate buffer. Since the pKafor dexmedetomidine is about 7.1, at this pH the molecule might beprotonated sufficiently to retard adsorption. Post-autoclave potencyvalues dropped approximately 10% in all instances; this was animprovement from the 20% decrease observed in the unbuffered formulationin Example 1.

In a second study, additives were formulated with the premixeddexmedetomidine composition to prevent adsorption of the dexmedetomidineto CR3 elastomer copolyester ether (Hospira, Inc., Lake Forest, Ill.).The following additives were tested: ethyl alcohol, benzyl alcohol,methyl paraben, propyl paraben, PEG 1000, polysorbate 20 and 80,propylene glycol. Formulations prepared included additives in bothbuffered and unbuffered premixed dexmedetomidine composition. Both thesereformulation strategies reduced potency loss.

Stability testing of the 4 μg/mL premixed dexmedetomidine composition(unbuffered saline formulation), in glass vials and ampoules stored at25° C., after 9 months was performed. Potency remained relativelyunchanged from initial measurements. Additionally, the largest singleimpurity detected in the samples was present at a concentration of0.06%.

Example 4 Stability of the Premixed Dexmedetomidine Composition

The stability of dexmedetomidine hydrochloride to acidic, basic,oxidative and photolytic stress was examined. In order to demonstratethe resiliency of dexmedetomidine, even when present in extremely lowlevels (ppm or μg/mL levels), dilute solutions of dexmedetomidine(approx. 13.3 μg/mL) were separately subjected to acidic, basic,oxidative and photolytic stress and then diluted with 0.9% SodiumChloride to a final nominal concentration of 4 μg/mL and assayed by HPLCwith a photodiode array (PDA) detector for spectral peak purityanalysis. Each sample was injected in duplicate. The stress conditionsare listed in Table 4.

TABLE 4 Stress Conditions Stress Condition Description Acid 5.0 mL of a40 μg/mL stock Dexmedetomidine Hydrochloride solution* and 10 mL of 5NHydrochloric Acid were added to 20 mL scintillation vial. The vial wasplaced in an oven at 60° C. for 8 hours. The solution was then dilutedwith 0.9% NaCl to 4 μg/mL. Base 5.0 mL of a 40 μg/mL stockDexmedetomidine Hydrochloride solution* and 5 mL of 2N Sodim Hydroxidewere added to 20 mL scintillation vial. The vial was placed in an ovenat 60° C. for 4 hours. The solution was then diluted with 0.9% NaCl to4μg/mL. Thermal 5.0 mL of a 40 μg/mL stock Dexmedetomidine Hydrochloridesolution* was added to 20 mL scintillation vial. The vial was placed inan oven at 60° C. for 8 hours. The solution was then diluted with 0.9%NaCl to 4 μg/mL. H₂O₂ 5.0 mL of a 40 μg/mL stock DexmedetomidineHydrochloride solution* and 5 mL of 0.3% Hydrogen Peroxide were added to20 mL scintillation vial. The vial was placed in an oven at 60° C. for 8hours. The solution was then diluted with 0.9% NaCl to 4 μg/mL. Light5.0 mL of a 40 μg/mL stock Dexmedetomidine Hydrochloride solution* wereadded to 20 mL scintillation vial and placed into a photochemicalreaction unit for 24 hours. The solution was then diluted with 0.9% NaClto 4 μg/mL. Control 5.0 mL of a 40 μg/mL stock DexmedetomidineHydrochloride solution* was added to 20 mL scintillation vial. The vialwas not subjected to any stress condition. The solution was then dilutedwith 0.9% NaCl to 4 μg/mL. *Stock solution of dexmedetomidine HCl wasprepared in 0.9% NaCl solution.

The peak purity analysis shows that under all stress conditions theparent peak were spectrally pure, attesting to the assay being performedunder conditions of specificity. See Table 5 for Potency Results.

Under oxidative conditions, the sample showed highest amount ofdegradation (12.7%) compared to the control sample. Appropriateprecautions are taken during manufacturing and packaging to preventoxidative stress.

Thermal stress studies indicate that the premixed dexmedetomidinecomposition is stable at high temperature. It is also confirmed byaccelerated stability studies, wherein potency values remained withinshelf life specifications over a period of 6 months. Moreover thepremixed dexmedetomidine composition is a terminally sterilized product.Hence, it is expected that premixed dexmedetomidine composition wouldremain stable if exposed to temperature excursions during transportationor storage.

TABLE 5 Forced Degradation Results Samples ID Assay Control Sample 98.4%Acid Sample 95.2% Base Sample 93.8% Heat Sample 98.4% Oxidation Sample85.7% Light Sample 92.0%

Example 5 Manufacture of the Premixed Dexmedetomidine CompositionFormulation

A 4 μg/mL premixed dexmedetomidine composition can be manufacturedaccording to the following process: Water for Injection is added to amixing tank to approximately 110% of the final volume and heated to 80°C. Nitrogen sparging in the tank is started and maintained throughoutthe manufacturing process. Water for Injection is then cooled and asufficient amount of water is withdrawn from the tank to leaveapproximately 90% of the final volume in the mix tank. DexmedetomidineHCl is then added to the tank and mixed for not less than 15 minutes.Sodium chloride is then added and mixed. The solution is then dividedinto batch size. An in-process sample is then evaluated for pH andpotency. The nitrogen protection is maintained.

Filtering of Dexmedetomidine Composition

The dexmedetomidine solution is filtered prior to filling in aclinician-useable container. For the 20 mL batches, solution is filteredthrough Pall Nylon 66, 0.45 μm filter membrane with a pre filter. For 50and 100 mL batches, solution is filtered through Nylon 66, 0.22 μmfilter membrane with a pre filter. A filter compatibility study wasperformed using Pall Nylon 66 0.45 μm filter. It was determined thatfilters had little to no impact on the premixed dexmedetomidinecomposition product after 52 hours of recirculation. The prolongedexposure of these filter materials did not produce any significantpotency or pH changes in the drug product (See Table 6). Additionally,there was no change in bubble point for the filters before and afterexposure.

TABLE 6 Filter compatibility testing Pall Nylon 66 filter (Pall Corp.,Port Washington, NY) Time Sample Tested Potency (%) pH Pre-filtrationTank (0 hr) 99.8 6.30 5 minute static filter hold 97.3 6.01 sample Onehour tank 99.4 6.17 Six hour tank 99.1 6.18 Eight hour tank 99.2 6.23 25hour tank 98.9 6.24 52 hour tank 99.3 6.17Nitrogen Protection During Filling

The transfer line from solution manufacturing to filling is optionallyflushed with filtered nitrogen gas prior to filling. The fillingequipment, including all lines are purged with nitrogen before startingto fill the product. An atmosphere of filtered nitrogen gas ismaintained in the headspace of the surge bottle. After filling, theheadspace of the container is gassed with nitrogen to achieve not morethan 5% of oxygen in the headspace.

Hold Time

The following time limits will be applied to manufacture of the subjectdrug product:

Total time for filtration and filling: NMT (Not More Than) 16 hours

Total time for manufacturing (from compounding to end of filling): NMT24 hours

Sterilization

The premixed dexmedetomidine composition is terminally sterilized. Vialsfilled with the composition are autoclaved using 15-30 minutes exposureat 121-124° C.

Container Closure System

The 4 μg/mL premixed dexmedetomidine composition can be manufactured inthree configurations: 20 mL fill in 20 mL vial, 50 mL fill in 50 mL vialand 100 mL fill in 100 mL vial. Examples of packaging components for the20 mL, 50 mL and 100 mL configurations are listed in Tables 7, 8, and 9below.

TABLE 7 Container Closure System for 4 μg/mL Premixed DexmedetomidineComposition, 20 mL Primary Packaging Materials Kimble USP Type I, ClearTubing Glass Vial, Sulfur-Treated, 20 mm, 20 mL (Kimble Chase, Vineland,NJ) West 4432/50 Teflon 2 coated Gray rubber Closure (Stopper), 20 mm(West Pharmaceutical Services, Inc.) Seal, Flip-Off ® (Blue or Gray)elastomer stoppers, 20 mm (West Pharmaceutical Services, Inc.,Lionville, PA)

TABLE 8 Container Closure System for 4 μg/mL Premixed DexmedetomidineComposition, 50 mL Primary Packaging Materials Gerresheimer USP Type I,Glass Vial (Bottle), Sulfur-Treated, 28 mm, 50 mL (Gerresheimer GlassInc., Vineland, NJ) Helvolet FM 259/0 Gray with OmniflexPlus ®Fluoropolymer coating Rubber Closure (Stopper), 28 mm (Helvoet Pharma,Datwyler USA, Pennsauken, NJ) Aluminum Seal, Overseal Assembly, 3 piece,28 mm

TABLE 9 Container Closure System for 4 μg/mL Premixed DexmedetomidineComposition, 100 mL Primary Packaging Materials Gerresheimer USP Type I,Glass Bottle, Sulfur-Treated, 100 mL (Gerresheimer Glass Inc., Vineland,NJ) Helvolet FM 259/0 Gray with OmniflexPlus ® Fluoropolymer coatingRubber Closure (Stopper), 28 mm (Helvoet Pharma, Datwyler USA,Pennsauken, NJ) Aluminum Seal, Overseal Assembly, 3 piece, 28 mmBatch Formula

Examples of qualitative and quantitative batch formula for aregistration batch and a commercial batch for a 4 μg/mL premixeddexmedetomidine (dexmedetomidine hydrochloride) composition, for a 20,50, and 100 mL presentation are presented in Tables 10 and 11 below.

TABLE 10 Batch Formula for 4 μg/mL Premixed DexmedetomidineHydrochloride Composition, 20 mL Registration Maximum Stability BatchCommercial Batch Component Size: Size: Dexmedetomidine HCl 2.832 mg25.96 mg Sodium Chloride 5.4 g 49.5 g Water for Injection q.s. to 600Liters q.s. to 5500 Liters USP Nitrogen NF³ A.R. A.R. q.s. = Quantitysufficient A.R. = As requiredFactored to 100% basis.The final pH range of the finished product is 4.5-7.0.Nitrogen is used to displace air during manufacturing (i.e. to blanketthe formulation and to fill the vial headspace).

TABLE 11 Batch Formula for 4 μg/mL Premixed DexmedetomidineHydrochloride Composition, 50 & 100 mL Registration Maximum StabilityBatch Commercial Batch Component Size: Size: Dexmedetomidine HCl 4.72 mg33.04 mg Sodium Chloride 9 g 63 g Water for Injection q.s. to 1000Liters q.s. to 7000 Liters USP Nitrogen NF³ A.R. A.R. q.s. = Quantitysufficient A.R. = As requiredFactored to 100% basis.The final pH range of the finished drug product is 4.5-7.0.Nitrogen is used to displace air during manufacturing (i.e. to blanketthe formulation and to fill the vial headspace).In-Process Specification

Examples of in-process controls during the manufacturing process for the4 μg/mL premixed dexmedetomidine composition are presented in Table 12.

TABLE 12 In-Process Specification In-Process Procedures or In-ProcessUnit Operation Control/Test Methods Limit Solution Preparation pH USP<791> 4.5-7.0 (Compounding) Assay HPLC 94-106% Filling ProcessWeight/volume Perform fill weight/ Meets control volume checks perrequirements SOPAn example of final product limits for physical, chemical, andbiological testing of 4 μg/mL premixed dexmedetomidine composition arelisted in the Table 13.

TABLE 13 Premixed Dexmedetomidine Composition Specifications TestAcceptance Criteria Clarity Solution is clear. Solution does not containone or more particles visible upon attentive inspection Assay90.0%-110.0% (9.00 mg/mL-1.10 mg/mL) Color Colorless pH 4.5-7.0 VolumeLabel Claim Acceptable Range 20 mL 20.5-22.5 mL 50 mL 50.0-54.5 mL 100mL 102.0-10.8.0 mL Optical Purity NMT 1.0% Related Substances: A.Individual A. NMT 0.5% B. Total B. NMT 1.0% Sodium Chloride 90.0% -110.0% (8.1 mg/mL-9.9 mg/mL) Particulate Matter NMT 25/mL ³ 10 mm NMT3/mL ³ 25 mm Sterility Meets USP requirements Bacterial Endotoxin NMT0.08 EU/mL

Example 6 Stopper Selection for Glass Vials

The objective was to have three presentations of Precedex®(dexmedetomidine hydrochloride, Hospira, Inc., Lake Forest, Ill.) premixInjection 4 ug/mL: 20 mL, 50 mL and 100 mL. Precedex® concentrateInjection 100 μg/mL is currently marketed in 2 mL glass vial with West4416 Teflon coated elastomer stopper (West Pharmaceutical Services,Inc., Lionville, Pa.).

Uncoated infusion stoppers, were evaluated. 28 mm Helvoet 5330 rubberstopper (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.), EDPM rubberstoppers (EPSI, Franksville, Wis.) and West 4432 elastomer stoppers(West Pharmaceutical Services, Inc.) were investigated. Duringfeasibility testing loss of potency and stopper extractables wereobserved. The performance of coated stoppers was compared with that ofuncoated stoppers (West 4432 and Helvoet 5330) by conducting feasibilitystudies on West 4588/40 FluoroTec® elastomer stoppers (WestPharmaceutical Services, Inc., Lionville, Pa.). Results showed a clearbenefit to using a coated stopper vs. the uncoated stopper. The potencyremained stable with the coated stopper. Hence for Precedex® Injection,it was planned to implement coated stoppers in order to mimic thecurrent product and prevent any drug adsorption.

Helvoet FM 259/0 OmniflexPlus® fluoropolymer coated rubber stoppers(Helvoet Pharma, Datwyler USA, Pennsauken, N.J.) were evaluated.Chemical compatibility testing was favorable; upon autoclave no changein potency or pH was observed and no significant amount of impuritiesdetected. The OmniflexPlus® coated stopper from Helvoet, was examinedfor determining the self sealing characteristics of the stopper whenpenetrated multiple times with hypodermic needle. This is a dye ingresstest. The new stopper/vial/3-piece overseal combination passed thistest. Helvoet OmniflexPlus® coated stopper passed the Rocky Mountpressure test at the required 80 psi criterion. These stoppers, vialsand overseals were also evaluated by Tech Ops for functional testing toconfirm that the stoppers can be pierced without being pushed into thevial. All testing indicated that the stoppers are acceptable for use.

Feasibility stability studies were conducted by preparing a batch ofPrecedex® Injection 4 μg/mL and filling into 50 mL vials with theHelvoet OmniflexPlus® stoppers followed by autoclaving. Samples werestored under accelerated (40° C./75% relative humidity, inverted) andlong term (25° C./60% relative humidity) conditions. Initial testingshowed no loss in potency, no change in pH, and virtually no measurableimpurities. The 1 month stability testing of samples stored inverted at40° C. showed slight drop in potency (2%). This trend in potency dropcontinued at 2 months under accelerated conditions with further 2% dropin potency. After 3 months under accelerated conditions the potencyvalues remain unchanged as compared to that of 2 months, indicating thatpotency values have leveled off. Similar trend in drop of potency duringthe first three months of storage was observed for long term stabilityconditions (25° C./60% relative humidity) but the percent drop was less.The total percent drop in potency over three months under long termconditions was 1.1%. Stability testing at 4 and 5 months for samplesstored under accelerated and long term conditions confirmed that potencyvalues had almost leveled off, with small drop in potency values. During1 month impurity testing numerous small impurity peaks that totaled over0.5% of the drug peak were observed. A placebo batch was prepared toconfirm whether the peaks are related to the stopper or the drug.Results indicated that impurities were related to the stopper.

Plastic vials were also evaluated for Precedex® premix Injection 4mcg/mL. Two types of plastic vials were used: CZ resin and polypropylene vials. West 4432 Teflon coated 20 mm elastomer stopper (WestPharmaceutical Services, Inc.) was used for both the plastic vials. ThepH, potency and impurities of Precedex® Injection 4 mcg/mL filled inplastic vials and stored under accelerated conditions over a period of 3months was determined. Similar trend in potency drop was observed. Thetotal % impurities were found to increase over a period of 3 months forboth CZ resin vials and polypropylene vials, but the total % ofimpurities of CZ resin vials was less than that of polypropylene vials.CZ resin vials were found to better as compared to polypropylene vialsin terms of drop in potency and total impurities.

Since the drug is present at such a low concentration 4 μg/mL, even ppblevels of impurities would have a significant contribution toward theimpurity limit. Moreover the Precedex® related substances method wasdeveloped to detect organic impurities at ppb levels. This methodrequires detection at non-discriminating low wavelength of 210 nm andhigh injection volume of 500 μl, which render it highly sensitive todetect any organic impurity, including stopper extractables.

Extractables

West 4432/50 Teflon 2 Coated Elastomer Stoppers (West PharmaceuticalServices, Inc.)

The West 4432/50 Teflon 2 coated elastomer stopper, 20 mm is used forPrecedex® Injection 4 μg/mL, 20 mL presentation. The stoppers have beenqualified for use based on the results of compendial biological,physiochemical and other characterization tests. The related substancetesting of Precedex® Injection has not shown any unidentified peaks thatexceed the specification of NMT 0.2%, suggesting that extractables arenot an issue for Precedex® Injection in this container closure system.

Helvoet FM 259/0 Omniflex® Fluoropolymer Coated Rubber Stoppers (HelvoetPharma, Datwyler USA, Pennsauken, N.J.)

The Helvoet Omniflex® fluoropolymer coated FM259/0 gray bromobutyl 28 mmrubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.)(ready-to-use) are used for Precedex® Injection 4 μg/mL, 50 and 100 mLpresentations. The stoppers have been qualified for use based on theresults of compendial biological, physiochemical and othercharacterization tests performed

During related substances analysis of the exhibit batches of Precedex® 4μg/mL Injection, unidentified impurity peaks were observed inchromatograms of 50 and 100 mL presentation samples. Duringinvestigation of the source of chemical constituents responsible for the‘unidentified impurity peaks’, it was found that these peaks alsoappeared in chromatograms of 0.9% NaCl placebo formulation filled into50 mL vials with Helvoet FM259/O rubber stoppers (Helvoet Pharma,Datwyler USA, Pennsauken, N.J.), but were absent in those of 0.9% NaClplacebo formulation filled into glass ampoules. Additionally identicalpeaks were observed in chromatograms of Helvoet FM259/O rubber stopper(Helvoet Pharma, Datwyler USA, Pennsauken, N.J.) extract solutionanalyzed by Precedex® related substances method. The extract wasprepared by autoclaving (121° C. for 60 minutes) 30 stoppers in 300 mLpurified water, yielding an extract of 2 cm² stopper surface area per mLwater. The results from these investigative studies confirmed that‘unidentified impurity peaks’ observed at specific relative retentiontimes were not dexmedetomidine HCl related, but were extractables fromHelvoet rubber stoppers used in the container/closure system. It wasexpected that stopper extractables would be detected at such low limitsof detection, i.e. ppb levels, as a highly sensitive LC-UV 210 nmrelated substances method was used for a highly potent very lowconcentration (4 μg/mL) product.

The chemical constituents responsible for peaks in specific relativeretention times were determined to be extractables from 28 mm HelvoetFM259/O rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken,N.J.), part of container closure system for Precedex® Injection 50 and100 mL. Moreover no peaks were found in these specific relativeretention times in chromatograms of forced degradation samples ofdexmedetomidine HCl or Precedex® Injection filled in ampoules. Hence inthe calculation of single largest related substance and total relatedsubstances, peaks in relative retention time ranges: 0.71-0.80,1.10-1.30, 1.50-1.80 are excluded.

In an effort to quantify the highest levels of observed individualextractable and total extractable, dexmedetomidine HCl was used as asurrogate standard for all stopper extractables. Since, the HelvoetFM259/O rubber stopper (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.)extractables responsible for the peaks in Precedex® related substancesprofile could not be identified. Through 6 months stability testing thehighest % of extractables was observed in Precedex® stability samplesstored at 30° C./65% relative humidity for 3 months. The largestindividual extractable % peak area was found to be 0.95% or 38 ppb andtotal extractable % peak area, calculated by adding the % peak areas ofall the peaks in the RRT of 0.71-0.80, 1.10-1.30, 1.55-1.80, was foundto be 2.7% or 108 ppb.

Helvoet FM259/O rubber stoppers (Helvoet Pharma, Datwyler USA,Pennsauken, N.J.) passed the ‘Elastomeric Closures for Injections’testing. As per Helvoet technical documentation the total amount ofextractables was determine to be 0.8 mg/100 mL or 8 ppm for a totalsurface area of 100 cm². The surface area of a 28 mm Helvoet stopper isapproximately 6.45 cm², the total acceptable amount of extractable foreach 28 mm Helvoet FM259/O rubber stopper (Helvoet Pharma, Datwyler USA,Pennsauken, N.J.) on an average would be 0.05 mg/100 mL or 500 ppb.Additionally as per USP the total organic content of purified watershould not exceed 0.5 mg/L or 500 ppb. The highest levels of observedextractables in Precedex® Injection are at least 5 times lower than theacceptable levels of extractable in purified water and acceptable levelsof extractable in the qualified Helvoet stoppers.

USP ‘In vitro cytotoxicity test’ and USP ‘Intracutaneous test andsystemic injection test’ were performed on Helvoet stopper extracts. Theresults show that stoppers meet the requirements of these tests,confirming the safety of the stoppers and any stopper relatedextractables. The ‘In vitro cytotoxicity test’ was repeated for Helvoet28 mm stoppers that were used in the exhibit batch to demonstrate thesafety of the stoppers. The stopper extract was prepared by autoclavingthe stoppers at 121° C. for 1 hour in 0.9% NaCl yielding an extract of 2cm² stopper surface area per mL water. This extraction condition closelymimics Precedex®Injection manufacturing conditions and also meets theextraction requirements of USP ‘In vitro cytotoxicity test’ testing.Precedex® injection is formulated in 0.9% NaCl and the final producti.e. Precedex® Injection in container-closure is autoclaved at 121° C.for 20-40 minutes. Additionally while investigating the source of‘unidentified impurity peaks’ Helvoet FM259/O rubber stopper (HelvoetPharma, Datwyler USA, Pennsauken, N.J.) aqueous extracts were preparedby autoclaving the stoppers at 121° C. for one hour and then tested bythe Precedex® related substances method. The results demonstrated thatthe chemical constituents responsible for the peaks were also present inthe Helvoet FM259/O rubber stopper (Helvoet Pharma, Datwyler USA,Pennsauken, N.J.) aqueous extracts. The stoppers passed the USP 87testing indicating that the stopper extractables are non cytotoxic.

According to Helvoet Pharma, Helvoet FM259/O Omniflex® fluoropolymercoated rubber stoppers (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.)have been used for other marketed products, and there have been noreported cases of toxicity issues arising due to stopper extractables.

Identification of Extractables

Diligent efforts were made to characterize and identify theextractables. Helvoet's extractables report lists a number of potentialextractable compounds. From Helvoet's list, the most likely to beresponsible for the peaks observed in the Precedex® chromatograms wereselected:

BHT

Irganox-1076

Irganox-1010

Stearic Acid

Palmitic Acid

Sulphur

Samples of these compounds were obtained, and solutions were preparedand injected into an HPLC using the Precedex® related substances method.None of these compounds matched the relative retention time of thestopper extractable peaks in Precedex® sample chromatograms. In general,the substances listed above are all too hydrophobic (retained too longon the C18 column with the isocratic mobile phase that is used for themethod, 40% aqueous phosphate buffer pH 7.0/60% methanol).

Since these peaks were also observed in the chromatograms of HelvoetFM259/O rubber stopper (Helvoet Pharma, Datwyler USA, Pennsauken, N.J.)extract solution, a concentrated stopper extract solution was preparedby first by autoclaving a large number of stoppers in purified water,and then concentrating the extract by liquid-liquid extraction intodichloromethane and then rotovaping and re-suspending the residue into asmall volume of methanol/water. LC-UV analysis of this concentratedstopper extract show the same peaks of interest as observed in Precedex®chromatogram, but at much higher levels (approx 100 times larger peaksize). This concentrated extract solution was then analyzed by LC-MSusing the Waters Q-TOF instrument with the electrospray source inpositive ion mode and observed at least one of the peaks of interest inthe mass spec TIC chromatogram; the mass spectrum of the peak has beenobtained and appears to have what might be the molecular ion peak at m/z158; exact mass analysis of this peak and its pattern of isotope peakspredicts some empirical formulas. Compounds with these empirical formulaand known usage in the rubber industry were tested but without success.

Solvent extracts of the stoppers were prepared and analyzed by gaschromatography-mass spectrometry. Analysis revealed the presence of twolow molecular weight rubber oligomers previously reported by Helvoet.These oligomers are not commercially available for identificationconfirmation; however, their hydrophobic character makes it unlikelythat they would elute near dexmedetomidine in the related substancesHPLC method.

A pure extractable sample was isolated by combining multiple fractionscollected from repeated HPLC separations of a stopper extract. Attemptsto obtain an EI+ mass spectrum by direct probe mass spectrometry and gaschromatography-mass spectrometry were unsuccessful, suggesting that thestopper extractable is nonvolatile and possibly thermally labile.

The pure extractable sample was analyzed by IR and elemental analysis.Both of these techniques suggested that the extractable contains onlycarbon, oxygen and hydrogen. No indication of nitrogen, sulfur or anyother heteroatom was observed.

The chemical additives that perform variety of functions, includingplasticizers, fillers, etc are the most significant source of chemicalentities observed as extractables. There are several reasons which makesidentifying the extractables challenging and at times impossible. Eachfunctional additive category contains representatives from severalmolecular structures. For example, consider the category ofantidegradants, subcategory antioxidants, which includes aromaticamines, sterically hindered phenols, phosphites, phosphonites, andthioethers. To further complicate the picture, chemical additives areoften not pure compounds but mixtures of related structures. Forexamples “Abietic Acid” which is an organic chemical filler used incertain types of rubber, in reality is a complex mixture of chemicalentities, all of which could appear as extractables/leachables. Chemicaladditives can also react and degrade within the rubber/polymer matrixduring or subsequent to compounding process. As an example of thisconsider, the trivalent phosphorus, or phosphate antioxidant, a commontradename for which is Irgafos 168. This compound reacts with andthereby destroys oxidizing agents, such as hydroperoxides, to form thecorresponding pentavalent phosphorus species, or phosphate.

In addition to the foregoing, the following must also be considered whenanalyzing extractables/leachables:

Monomers and high molecular weight oligomers derived from incompletepolymerization reactions.

Surface residues, such as heavy oils and degreasing agents on thesurface of metal canisters and containers.

Chemical additives on the surfaces of container closure componentfabrication machinery, such as mould release agents, antistatic andantislip agents, etc.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

Patents, patent applications, publications, product descriptions, andprotocols are cited throughout this application, the disclosures ofwhich are incorporated herein by reference in their entireties for allpurposes.

1. A ready to use liquid pharmaceutical composition for parenteraladministration to a subject, comprising dexmedetomidine or apharmaceutically acceptable salt thereof at a concentration of about 4μg/mL disposed within a sealed glass container.
 2. The ready to useliquid pharmaceutical composition of claim 1, further comprising sodiumchloride at a concentration of between about 0.01 and about 2.0 weightpercent.
 3. The ready to use liquid pharmaceutical composition of claim2, wherein the sodium chloride is present at a concentration of about0.9 weight percent.
 4. The ready to use liquid pharmaceuticalcomposition of claim 1, wherein the composition is formulated as a totalvolume selected from the group consisting of 20 mL, 50 mL and 100 mL.